Bone plays an important role of not only a supporting organ or motility organ of the living body, but also a reservoir organ of Ca2+. To perform such functions, bone formation by osteoblast and bone resorption by osteoclast are repeated in bone tissues, whereby old bone is constantly substituted by a new bone and the strength of the whole bone is maintained.
It is considered that when bone formation and bone resorption are imbalanced, a decrease in the bone mass and degradation of the bone tissues occur, which in turn leads to the affection with bone diseases such as osteoporosis, fibrous osteitis(hyperparathyroidism), osteomalacia, Paget's disease, chronic articularrheumatism, arthritis deformans and the like. Particularly, osteoporosis is often found in elderly people and women, and 11 million patients are assumed to be present in Japan and not less than 30 million patients in the United States. The symptoms include bone fracture and pain such as lumbago and the like, which may produce bedridden patients, body deformation, and bone fracture such as hip fracture and the like, which could be fatal depending on the fracture site.
Therapeutic drugs for osteoporosis include bone resorption inhibitors that suppress osteoclast activity and bone formation promoters that activate osteoblast. As the bone resorption inhibitor, calcitonin, bisphosphonate, estrogen receptor modulator and the like are used. However, these therapeutic drugs prevent a further decrease in the bone mass but cannot reconstruct lost bones. On the other hand human PTH (1-34) is used as the bone formation promoter, which can be utilized for increasing the bone mass and bone density and reconstructing a bone structure. However, the use period is limited to one and a half years to two years, and subcutaneous injection is required for a long term, which is difficult for the patients to comply.
Thus, the development of an orally administrable bone formation promoter having a high clinical effect has been desired.
Recently, benzothiepin derivatives having an alkaline phosphatase-inducing activity (patent document 1, 2), N-quinolylanthranilic acid derivative (patent document 3), triazolopyridazine derivative (patent document 4), thienopyridine derivative (patent document 5) and [5,6]heterocyclic compound (patent document 6) have been reported to be useful for the treatment of diseases associated with promoted bone formation and bone metabolism. However, its clinical usefulness is unknown.